Abstract Breast cancer is extremely common, striking 1 in 8 American women, and is the second leading cause of cancer death among women in the U.S. Women with dense breasts on screening mammography have a two to five times increased risk of developing breast cancer, and increased breast density reduces the sensitivity of mammography for cancer detection. As a result, a growing number of states have passed legislation mandating that women have a right to know if their breast density is increased. Unfortunately, there are no clear guidelines as to what women should do with this information or appropriate supplemental screening strategies. Studies investigating the use of ultrasound in this role have not been convincing, generally showing low added cancer yield and high rate of false positives. On the other hand, contrast-enhanced MRI has the highest sensitivity for detecting cancers in dense breasts, but barriers to more widespread use of breast MRI include high costs, relatively lengthy scanning times, and contraindications related to administration of gadolinium-based contrast. Furthermore, new research providing evidence of accumulation of gadolinium- based contrast agents in the brain has raised awareness and concerns about the risk of long-term use of contrast-enhanced MRI for screening and surveillance. An effective, low cost, safe screening method is needed to detect mammographically occult cancers in women with dense breasts. Diffusion-weighted imaging (DWI) is a short (2-3 minutes) non-contrast MRI technique that has shown promise for the detection and characterization of breast cancer. Our preliminary data has shown that DWI holds potential for detecting mammographically and clinically-occult breast cancers. However, current technical limitations reduce the sensitivity of DWI for screening applications. We hypothesize that an optimized DWI approach will enable detection of mammographically occult breast cancer in women with dense breasts with high sensitivity and low false positive rate. Aims of the study will be to 1) optimize the DWI acquisition 2) develop an interpretation strategy and tools, and 3) test the performance of DWI for detecting mammographically-occult breast cancer in women with dense breasts. If successful, non-contrast DWI could provide a viable supplemental screening tool to improve early detection of cancer in women with dense breasts.